As a consequence of the widespread use and perhaps even misuse of antibacterial drugs, strains of drug-resistant pathogens have emerged. Antibiotic-resistant bacterial strains have been associated with a variety of infections, including tuberculosis, gonorrhea, staphylococcal and pneumococcal infections, and the bacteria most commonly associated with pneumonia, ear infections and meningitis. More importantly, infectious disease remains the largest cause of mortality in the world.
The typical response to an ineffective antibiotic has simply been change antibiotics. Unfortunately, this alternative no longer offers a guarantee of success. For example, certain strains of enterococci are resistant to vancomycin--a drug formerly considered to be the ultimate weapon against many different types of bacteria. The World Health Organization has expressed concern that the development of new drugs is not keeping pace with the numbers of antibiotics which become ineffective. World Health Report 1996: Fighting Disease, Fostering Development, Executive Summary (World Health Organization 1996). Despite ongoing research, there remains a pressing need to develop new antibiotics. There is also a need for antibacterials that are effective in treating disease while not stimulating the emergence of resistant strains.
Bacteria respond to nutritional stress by the coordinated expression of different genes. This facilitates their survival in different environments. Among these differentially regulated genes are the genes responsible for the expression of virulence determinants. The expression of these genes in a sensitive or susceptible host allows for the establishment and maintenance of infection or disease. Virulence genes encode toxins, colonization factors and genes required for siderophores production or other factors that promote this process.
Virulence genes in bacteria express a variety of factors that allow the organism to invade, colonize and initiate an infection in humans and/or animals. These genes are not necessarily expressed constantly (constitutively), however. That is, the bacterium is not always "infectious". In many circumstances, the expression of virulence genes is controlled by regulatory proteins known as repressors in conjunction with a corresponding operon(s) or operator(s). In prokaryotes, one class of repressors is activated upon binding to or forming a complex with a transition metal ion such as iron or zinc. When the repressor is activated, it binds the operator thereby preventing production of virulence determinants.
Virulence determinants are most often expressed when the bacterial pathogen is exposed to nutritional stress. An iron-poor environment is an example of such a condition. In this environment, insufficient iron is present to maintain the repressor in its active state. In the inactive form, the repressor cannot bind to target operators. As a result, virulence genes are de-repressed and the bacterium is able to initiate, establish, promote or maintain infection.
The expression of these virulence determinants is in many bacterial species is co-regulated by metal ions. In many instances the metal co-factor that is involved in vivo is iron. In the presence of iron, the repressor is activated and virulence gene expression is halted.
This pattern of gene regulation is illustrated by the following example. The bacterium that causes diphtheria produces one of the most potent toxins known to man. The toxin is only produced under conditions of iron deprivation. In the presence of iron, the bacterial repressor (which in this species is known as diphtheria toxin repressor protein, abbreviated "DtxR") binds iron and undergoes conformational changes that activate it and allow it to bind a specific DNA sequence called the tox operator. The tox operator is a specific consensus DNA sequence found upstream of the gene that produces the diphtheria toxin. Binding of DtxR to this site thereby prevents toxin expression. Typically, during infection of a human or animal host the diphtheria bacillus (or other pathogenic/opportunistic bacteria) grows in an environment that rapidly becomes restricted in several key nutrients. Paramount among these essential nutrients is iron, and when iron becomes limiting the diphtheria bacillus begins to produce the toxin. Moreover, the constellation of virulence genes that DtxR controls becomes de-repressed and the diphtheria bacillus becomes better adapted to cause an infection. In the case of diphtheria, the toxin kills host cells thereby releasing required nutrients including iron.